Stroke is a leading cause of cardiovascular-related mortality and morbidity in the United States, and a substantial genetic contribution to this disease is widely accepted. We propose to identify genes whose effects are modified in the presence of smoking. We will focus on young-onset stroke (i.e., stroke onset before age 56), in whom genetic factors and smoking-associated risk may play an even larger role. A two-stage approach will be used, beginning with a genome-wide association study in 929 young-onset stroke cases and 936 controls accrued from population-based case-control studies at the University of Maryland over the past 20 years. The 1% most strongly associated SNPs will then be genotyped in the Stage 2 replication set, which will utilize 1,853 young-onset cases and 1,199 controls contributed by 9 participating sites from the International Stroke Genetics Consortium. In addition to its focus on young-onset stroke, our study has the strength of including both women and men, and African-Americans and Whites. The proposed study will complement studies of older stroke patients and will be a continuing resource for understanding the genetic basis of stroke risk and how this risk is modified by smoking. Lay summary: Stroke, defined as acute vascular disease of the brain, is the third leading cause of death and the leading cause of major disability. The long-range goal of our research is to characterize the genetic and environmental basis for stroke susceptibility in order to develop more effective prevention and treatment strategies.